Laboratory Features of Cutaneous Lupus Erythematosus 313

CHAPTER 23

Laboratory Features 23 of Cutaneous Lupus Erythematosus Shuntaro Shinada, Daniel J. Wallace

Assuming that patients with cutaneous lupus erythematosus (CLE) do not fulfill the American College of Rheumatology criteria for systemic LE (SLE) (Tan et al. 1982), what laboratory features should the clinician look for? Interestingly, there are several. This chapter attempts to elucidate the laboratory abnormalities associated with CLE, the most common being hematologic (anemia and leukopenia), erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANAs), and antiphospholipid antibodies. These features are compared with those observed in SLE and certain cutaneous clinical subsets that have been studied.

General Approach to Laboratory Testing

When a dermatologist, family practitioner, internist, or rheumatologist first sees a patient with CLE, their principal concern should be to rule out evidence of systemic disease. After all, 15% of patients with CLE progress to SLE in 10–15 years of obser- vation (Rowell 1984). In addition to a complete medical history and physical examination, clinical laboratory findings can be very helpful in this regard. Specifically, a blood chemistry panel allows screening for renal or hepatic involvement. Creatine phosphokinase testing assists in ruling out muscle inflammation. Evidence for autoimmune hemolytic anemia or thrombocytopenia is looked for in the complete blood cell count as well as in the lactic dehydrogenase, reticulocyte count, Coombs’ direct antibody testing, serum haptoglobin, and antiplatelet antibodies. A routine urinalysis free of cellular casts or protein makes it highly unlikely that the kidney is involved. Specific autoantibodies, almost never observed in CLE, if found, can suggest central nervous system disease (antiribosomal P,antineuronal), mixed connective tissue disease (anti-RNP), or other disease subsets. In our practice, all patients have annual chest radiographs and electrocardiograms, since there are no blood tests to screen for cardiac or pulmonary involvement. Finally, additional imaging or electri- cal tests (electromyography, nerve conduction studies, 2-D echocardiography with Doppler) are occasionally ordered, and the results should be normal in CLE. If not, muscle, nerve, cardiac, or pulmonary disease representing visceral involvement should be ruled out. This chapter assumes that the presence of systemic disease is not under consider- ation. The question remains, are there any laboratory tests worth ordering to monitor or better characterize CLE? 312 Shuntaro Shinada, Daniel J. Wallace

Medications Used to Manage Cutaneous Lupus Erythematosus Warrant Periodic Laboratory Monitoring

Although the different therapeutic options for CLE are discussed in later chapters, it is valuable to note the laboratory abnormalities associated with the medications used to treat CLE (Table 23.1).

Table 23.1. Laboratory abnormalities associated with use of drugs for cutaneous lupus erythematosus

Medication Laboratory side effects Laboratory monitoring

Antimalarials Monitor CBC, serum creatinine, Chloroquine Hemolysis secondary to and LFT every 2 months G-6-PD deficiency, decreased creatinine clearance Hydroxychloroquine Decreased creatinine clearance, decreased cholesterol profile, agranulocytosis (rare) Quinacrine Aplastic anemia Antileprosy drugs Dapsone Sulfhemoglobinemia, methe- Monitor baseline G-6-PD levels. moglobinemia, hemolysis Monitor CBC every 2 weeks for the secondary to G-6-PD defi- first 3 months, then every 2 months ciency, hepatotoxicity thereafter Monitor baseline LFTs then every 2 months thereafter Thalidomide Highly teratogenic, neutro- Baseline pregnancy test, then penia weekly for the first month, then monthly thereafter Monitor CBC every 2 months Methotrexate Blood dyscrasias, hepato- Monitor baseline LFTs, CBC, serum toxicity creatinine, then weekly until dose stabilized, then every 1–2 months thereafter Cyclosporine Increased serum creatinine Monitor 2 baseline creatinines, then level every 2 weeks for the first 3 months, then every month thereafter Azathioprine Thrombocytopenia, neutro- Monitor baseline CBC, LFTs, then penia, hepatotoxicity every 2 weeks for the first month, then every 1–3 months thereafter Glucocorticosteroids Increased serum glucose Monitor baseline lipid panel, CBC, level; increased VLDL-C, serum glucose and potassium, then HDL-C, and TG levels monitor serum/urine glucose every 3–6 months

CBC, complete blood cell count; G-6-PD, glucose-6-phosphate dehydrogenase; HDL-C, high- density lipoprotein cholesterol; LFTs, liver function tests; TG, triglyceride; VLDL-C, very-low- density lipoprotein cholesterol. Laboratory Features of Cutaneous Lupus Erythematosus 313

Antimalarials

The three antimalarials available at this time for the treatment of CLE are chloroquine, hydroxychloroquine, and quinacrine. Overall, these drugs are relatively safe, but there are some laboratory abnormalities to consider. Chloroquine slightly decreases creatinine levels in half of its users, most likely by raising plasma aldosterone levels (Musa- bayane 1994).Forty-five percent of hydroxychloroquine is excreted in the kidneys,and the drug is associated with up to a 10% decrease in creatinine clearance (Landewe et al.1995).Therefore,the dosage should be adjusted for patients with renal impariment. Antimalarials also have a beneficial antihyperlipidemic effect. Hydroxychloroquine induces a 15%–20% decrease in total cholesterol,triglyceride,and LDL levels (Wallace et al. 1990). It is associated with only one case of agranulocytosis, in a patient who was given 1,200 mg daily,which is up to six times the current recommended dosage (Polano et al. 1965), and a handful of case reports of various blood dyscrasias, such as aplastic anemia, leukopenia, thrombocytopenia, and hemolysis in individuals with glucose-6- phosphate dehydrogenase (G-6-PD) deficiency. Chloroquine has been implicated in rare reports of G-6-PD deficiency hemolysis (Choudhry et al.1978) and with agranulocytosis (Kersly and Palin 1959).Since chloroquine is known to concentrate in the liver, it should be used with caution in patients with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. The prevalence of aplastic anemia among US soldiers in the Pacific during World War II rose from 0.66 to 2.84 per 100,000 after quinacrine’s introduction (Custer 1946). This represented 58 patients, 48 of whom received quinacrine. Of these, 16 were associated with overdoses, and two received marrow-suppressant drugs concurrently (Wallace 1989). It is therefore recommended that patients receiving antimalarial treatment have a complete blood cell count and a serum creatinine test every few months during therapy. Patients taking chloroquine or hydroxychloroquine should undergo ophthalmologic examination at 6- or 12-month intervals, respectively.

Antileprosy Drugs Dapsone Dapsone’s use is limited by its toxic effects, which include sulfhemoglobinemia and methemoglobinemia, a dose-related hemolytic anemia, a “dapsone hypersensitivity syndrome,” and aplastic anemia (Meyerson and Cohen 1994, Mok et al. 1998). All patients treated with dapsone should have their baseline G-6-PD level checked. The drug should not be given to patients with low levels. Complete blood cell counts should be checked every 2 weeks for the first 3 months, then every 2 months thereafter. Toxic hepatitis and cholestatic jaundice have been reported early in therapy. Hyperbilirubinemia may occur more often in G-6-PD-deficient patients. Baseline and subsequent monitoring of liver function is recommended.

Thalidomide Thalidomide is a highly teratogenic drug with antileprosy and antilupus effects via various mechanisms.Side effects include teratogenicity,fatigue,dizziness,weight gain, constipation, amenorrhea, dry mouth, and a non-dose-related polyneuropathy that is associated with chronic administration (Ludolph and Matz 1982). Because thalido- 314 Shuntaro Shinada, Daniel J. Wallace mide is so highly teratogenic,women of childbearing potential should have pregnancy testing. The test should be performed within 24 h of beginning thalidomide therapy and at regular intervals when appropriate.Pregnancy testing should also be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. Decreased white blood cell counts, including neutropenia, have been infrequently reported in association with the clinical use of thalidomide. White blood cell count and differential should be monitored on an ongoing basis, especially in patients who may be more prone to neutropenia. Higher doses of thalidomide may predispose patients to coagulopathies.

Methotrexate Although serious and sometimes fatal blood dyscrasias are a well-known conse- quence of high-dose methotrexate therapy, the Committee on Safety of Medicines in the United Kingdom (Dodd et al. 1985) stated in September 1997 that it was also aware of 83 reports of blood dyscrasias associated with low-dose methotrexate used to treat psoriasis or rheumatoid arthritis; there were 36 fatalities. Megaloblastic anaemia, usually with marked macrocytosis, has been reported in mainly elderly patients receiving long-term weekly methotrexate therapy (Dahl 1984). Methotrexate has been associated with periportal fibrosis and cirrhosis (Neu- berger 1995), and its potential for hepatotoxicity has been a source of some concern given its use in nonmalignant disorders such as psoriasis and rheumatoid arthritis. It is recommended that liver function tests (LFTs) (as well as blood cell counts and renal function tests) be checked before beginning therapy then repeated weekly until therapy is stabilized, and thereafter every 2–3 months (Committee on Safety of Medi- cines/Medicines Control Agency 1994). The American College of Rheumatology rec- ommends checking baseline LFTs, along with complete blood cells counts, creatinine levels, and hepatitis B and C serologies, before initiating treatment; then, at intervals of 4–8 weeks, LFTs should be monitored (Kremer et al. 1994). Methotrexate should be used with great care in patients with bone marrow, hepatic, or renal impairment. Methotrexate is a potent teratogen, and its use should be avoided in pregnancy.

Cyclosporine Before initiating treatment, a careful physical examination, including blood pressure measurements (on at least two occasions) and two creatinine levels to estimate baseline status should be performed.Blood pressure and serum creatinine levels should be evalu- ated every 2 weeks during the initial 3 months and then monthly if the patient is stable. It is advisable to monitor serum creatinine levels and blood pressure always after an increase of the dose of nonsteroidal anti-inflammatory drugs and after initiation of new nonsteroidal anti-inflammatory drug therapy in those receiving cyclosporine treatment.

Azathioprine Thrombocytopenia and leukopenia are dose dependent and may be reversed by reducing the dose or temporarily discontinuing use of azathioprine. Other reported hematologic adverse effects include eosinophilia, leukocytosis, neutropenia, anemia, aplastic anemia, and fatal myelogenous leukemia. Laboratory Features of Cutaneous Lupus Erythematosus 315

Results of one small study suggest that analysis of thiopurine methyltransferase genotype may allow identification of patients who are at risk for azathioprine hematologic toxic effects. The authors consider testing to be cost-effective compared with the cost of blood monitoring and supportive care for the 2%–12% of patients with this toxic effect (Black et al. 1998). Data from the National Cooperative Crohn’s Disease Study identified six patients (5.3%) with pancreatitis who were treated with azathioprine alone (Sturdevant et al. 1979). Associated symptoms include abdominal pain, elevated amylase and lipase levels, and vomiting. Azathioprine can be hepatotoxic, and associated symptoms may include anorexia, nausea, fatigue, weight loss, jaundice, pruritis, dark urine, and elevated LFTs. Ideally, LFTs should be monitored every 2 weeks for the first 4 weeks and every 1–3 months thereafter (Gaffney and Scott 1998).

Glucocorticosteroids Glucocorticoids (GCs) induce insulin synthesis but oppose its effects on glucose metabolism, thus predisposing to or exacerbating, if present, diabetes mellitus. These effects take place because of decreased peripheral utilization of glucose and increased gluconeogenesis induction in the liver. GC enhances effects on lipolysis and protein catabolism, thus increasing the substrates for gluconeogenesis (Schimmer and Parker 1996). GCs have an impact on lipid metabolism by enhancing the lipolytic effect of catecholamines and growth hormone, and they induce a centripetal body fat redis- tribution (Orth and Kovacs 1998). One study showed that the administration of prednisone for 14 days in healthy men increased the levels of very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides (Ettinger and Haz- zard 1988).Another study showed that increasing the prednisone dose by 10 mg daily was associated with a 7.5-mg/dL increase in cholesterol levels (Petri et al. 1994). GCs induce peripheral neutrophilia and elevate white blood cell counts by reducing neu- trophil migration to tissues (Boumpas et al. 1993). Because of these effects of GCs, before starting therapy, it is recommended to check the baseline lipid panel (total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglyceride levels), complete blood cell count, and serum glucose and potassium levels. Thereafter, serum or urine glucose levels should be checked every 3–6 months. Since corticosteroids promote the excretion of water, some of its mineralocorticoid effects include hypokalemia, which should also be monitored.

Specific Laboratory Tests that Can Be Abnormal in Cutaneous Lupus Erythematosus

Please refer to Tables 23.2 and 23.3.

Hematologic Abnormalities Hematologic abnormalities are common in SLE and may often be its presenting manifestation. Although hematologic abnormalities are seen in CLE, they are not as 316 Shuntaro Shinada, Daniel J. Wallace

Table 23.2. Laboratory Differences Between the various subtypes of cutaneous lupus erythematosus (CLE). Modified from Sontheimer and Provost 1997

Disease features ACLE SCLE DLE

Antinuclear antibodies +++ ++ + Ro/SSA antibodies By immunodiffusion → + +++ 0 By ELISA → ++ +++ + Antinative DNA antibodies +++ + 0 Hypocomplementemia +++ + + Risk for developing SLE +++ ++ +

ACLE, acute CLE; DLE, discoid LE; ELISA, enzyme-linked immunosorbent assay; SCLE, subacute CLE; SLE, systemic LE. +++, strongly associated; ++, moderately associated; +, weakly associated; 0, negative, no association. common as in SLE. Patients with CLE had anemia ranging from 2% to 27% of the time, whereas patients with SLE had anemia 30% of the time. Eight percent of patients with SLE have hemolytic anemia, whereas it does not occur in patients with CLE (Pistiner et al. 1991). Between 0% and 30% of patients with CLE have leukopenia vs 51% of patients with SLE. Thrombocytopenia occurs in 2%–4% of patients with CLE as opposed to in 16% of those with SLE.

Erythrocyte Sedimentation Rate The ESR is a nonspecific marker for increased immunologic activity and is often time elevated in various types of inflammatory processes. The ESR is elevated in 20%–56% of patients with CLE, whereas it is elevated in most patients with SLE.

Antinuclear Antibodies The ANA test is a helpful serologic marker in the diagnosis of LE and other rheuma- tologic conditions. Approximately 96% of patients with SLE are positive for ANA, whereas 4%–63% of patients with CLE are positive for ANA. When reference labora- tories switched from using animal substrates to the HEp-2 cell line in the mid-1980s to detect ANA, many ANA-negative patients became positive. This may help explain why in studies done earlier than the mid-1980s, patients with CLE had lower ANA positivity rates than in those done after the mid-1980s.

Anticardiolipin Antibodies The anticardiolipin antibody is one of the serologic markers used to diagnose the antiphospholipid syndrome. The anticardiolipin antibody was positive in 31% of patients with CLE, whereas in patients with SLE its prevalence is slightly higher. Although anticardiolipin antibody is seen in 30%–40% of patients with SLE and CLE, it has not been associated with any complications (e. g., spontaneous abortions or arterial and/or venous occlusive disease) in CLE (Mayou et al. 1988). Laboratory Features of Cutaneous Lupus Erythematosus 317 Value, Wallace 1997 et al. 1992 P et al. 1975 al. et 1978 Rowell 1979 1982 1992 1991 enia (%) – – 4 – 2 16 0.0001 – Laboratory data comparing erythematosus (CLE) lupus cutaneous systemic and LE (SLE) rate (%) 56 45 20 43 31 54 0.001 56 (latex fixation)(latex (%) 1antibody (%) 6 – 13 – 21 – 9 – 23 31 0.02 38 0.53 – – ANAs, antibodies; antinuclear ds, double-stranded; RF, rheumatoid factor. Cases (n)YearAnemia (%)Hemolytic anemia (%)Leukopenia (%)Thrombocytop –Positive (%) 80 CLE ANAs C3 (%)Low 2High anti-ds-DNA (%) 0 1975 69Positive CLE anti-RNP (%) 4Positive – RF 0 – 92 CLEPositve anti-RoSSA 10 (%) 1978 8 14Positive anticardiolipin – 49 56 CLE –High 0 sedimentation 1979 – 27 12 67 CLE – 25 – 1982 0 – 464 SLE – 0 10 – 22 1990 – 0 4 5 30 7 1991 0 63 – 8 8 245 CLE 51 1991 2 30 10 96 4 0.009 40 0.002 14 0.0001 1997 39 0.0001 18 0.0001 – 0.081 – 0.0001 – 29 0.003 35 – – – Parameter Prystowski O’Loughlin Millard and Callen Wallace et al. et al. Pistiner CLE vs SLE Tebbe et al. Table 23.3. 318 Shuntaro Shinada, Daniel J. Wallace

Anti-Ro/SSA Antibody

Anti-Ro/SSA antibodies are present in the serum of patients with SLE and Sjögren’s syndrome and in 1 in 1,000 healthy people. The anti-Ro/SSA antibody is directed against ribonucleoproteins consisting of a 60-kDa peptide and an antigenically dis- tinct 52-kDa polypeptide. Positive anti-Ro/SSA antibody has been seen in 4% of patients with CLE, whereas in patients with SLE the prevalence is 18%–30%, depend- ing on whether immunoblotting or double diffusion methods are used. In a 1998 report by Chelbus et al. (Chelbus et al. 1998), there was similar frequency of both anti- Ro/SSA and anti-La/SSB in subacute cutaneous LE (SCLE) and SLE (approximately 70%). In another study, approximately 75% of patients with SCLE had anti-Ro/SSA precipitins (Sontheimer et al. 1982). Patients with SCLE have higher prevalence and titers of antibodies to both native 60-kDa Ro/SSA and 52-kDa Ro/SSA than those with chronic CLE (Lee et al. 1994).

Anti-double-stranded DNA Antibodies Autoantibodies to DNA are classically associated with SLE. Wallace et al. (Wallace et al. 1992) reported that 4%–8% of patients with CLE had high anti-double-stranded (ds) DNA antibodies (Farr assay) as opposed to 40% with SLE. Chelbus et al. (Chel- bus et al. 1988) noted that 1.2% of patients with SCLE had high anti-ds-DNA antibodies compared with 34% of patients with SLE.

Abnormal Testing Associated with Cutaneous Lupus Erythematosus Subsets Acute Cutaneous Lupus Erythematosus

ACLE refers to the acute inflammatory rashes in patients with SLE and as such, has not been studied as a separate entity. Wysenbeek et al. (Wysenbeek et al. 1992) noted that the nonspecific “rash” of SLE was associated with the presence of anti-ds-DNA antibodies and low serum complement.

Chronic Cutaneous Lupus Erythematosus Only a few patients with chronic CCLE without evidence of systemic involvement will have autoantibodies (Prystowsky et al. 1975). Of patients with CCLE, 30%–40% may exhibit low titers of ANA. However, fewer than 5% of patients with CCLE will have the higher levels of ANA that are seen in patients with severe SLE. Antibodies to single- stranded DNA are fairly common in CCLE,whereas antibodies to ds-DNA are uncommon (Callen et al. 1985). Patients whose disease course is dominated by discoid LE (DLE) lesions and who have evidence of mild SLE and overlapping connective tissue disease occasionally have precipitating antibodies to U1RNP (Callen 1982).Sometimes precipitating antibodies to Ro/SSA are seen in CCLE (Lee et al. 1994), and less frequently precipitating La/SSB and Sm antibodies (Provost and Ratrie 1990). Less than 10% of patients with CCLE have IgG isotype cardiolipin antibodies (Mayou et al.1988). Laboratory Features of Cutaneous Lupus Erythematosus 319

A small percentage of patients with CCLE will have a false-positive serologic test for syphilis (VDRL), positive rheumatoid factor, slight depression of serum complement levels, modest elevations in gamma globulin levels, or modest leukopenia.

Subacute Cutaneous Lupus Erythematosus SCLE occurs in 7%–27% of patients with LE (Cohen and Crosby 1994). Studies have shown that SCLE occurs mostly in white female patients in all age groups. Of patients with SCLE, 60%–81% have positive ANAs when human tissue substrate is used (Callen and Klein 1988). With immunodiffusion techniques, anti-Ro/SSA antibodies have been detected in 40%–100% of patients with SCLE (Lee et al. 1994). Anti-La/SSB antibodies by gel double diffusion have been observed in 12%–42% of patients with SCLE (Johansson-Stephansson et al. 1989). However, higher percentages of anti- La/SSB antibody levels have been seen in several studies outside the United States (Shou-yi et al. 1987). It has been reported that patients with SCLE have anti-ds-DNA at a prevalence of 1.2% (Chelbus et al. 1998). A false-positive syphilis serologic test result is detected in 17%–33% of patients with SCLE (Sontheimer 1989), and ca. 10%–16% of patients with SCLE have anticardiolipin antibodies (Fonesca et al. 1992). Rheumatoid factor is present in approximately one third of patients (Sontheimer 1989). Only 10% of patients with SCLE have anti-ds-DNA, anti-SmRNP, or anti-U1RNP antibodies (Sontheimer 1989). Approxi- mately one third of patients with SCLE have antilymphocyte antibodies, and 18%–44% of patients with SCLE are reported to possess antithyroid antibodies (Callen et al. 1986, Konstadoulakis et al. 1993).

Other Cutaneous Lupus Erythematosus Subsets Lupus Erythematosus Profundus/Lupus Erythematosus Panniculitis LE profundus/LE panniculitis is another rare form of CCLE characterized by inflammatory lesions in the lower dermis and the subcutaneous tissue. Of these patients, 70%–75% have positive ANA, but anti-ds-DNA antibodies are uncommon (Sanchez et al. 1982).

Chilbain Lupus Erythematosus/Lupus Pernio Chilbain LE/lupus pernio is another variant of CLE consisting of red-purple patches and plaques on patients’ faces, fingers, and toes that are precipitated by cold, damp climates. One study in 1998 found that eight of nine patients with chilbains lupus had anti-Ro/SSA antibodies (Franceschini et al. 1998). Most of these patients also com- plained of photosensitivity and Raynaud’s phenomenon.

Lupus Erythematosus Tumidus (LET), Hypertrophic Lupus Erythematosus, Mucosal Lupus Erythematosus LE tumidus (LET) is a subset of CLE seen when there is excessive accumulation of dermal mucin early in the course of a CLE lesion. The result is edematous, urticarial- appearing plaques of LE tumidus. Hypertrophic HLE (i.e., hyperkeratotic HLE, ver- rucous HLE) is a rare variant of CLE in which the hypekeratosis that is usually present in classic DLE is greatly exaggerated. Mucosal DLE is a variant of chronic 320 Shuntaro Shinada, Daniel J. Wallace cutaneous DLE involving most frequently the oral mucosa, as well as the nasal, con- junctival, and genital mucosal surfaces. The laboratory features of these three subsets of CLE are not well delineated.

Laboratory Testing and Progress to Dissemination of Systemic Lupus Erythematosus

Approximately 15% of patients with CLE eventually progress to SLE (Rowell 1984). Several studies have been undertaken to determine the clinical and laboratory features that may predict such a pattern of disease progression. Clinically, patients with generalized DLE are at higher risk of developing SLE, oftentimes with more severe manifestations (Callen 1982). Laboratory tests associated with the development of SLE in patients with DLE include severe leukopenia, unexplained anemia, false-positive serologic tests for syphilis, persistently positive, high-titer ANA, anti-single- stranded DNA antibody, hypergammaglobulinemia, an elevated ESR greater than 50 mm/h, and a positive lupus band test (Callen 1982). A study in 1997 showed that in SCLE and/or DLE, patients with evidence of nephropathy, arthralgias, or ANA titer of 1:320 were at significantly higher risk of having systemic disease (Tebbe et al. 1997). This study did not find ESR and anti-ds-DNA antibodies to be useful in distinguishing patients with or without systemic disease. Another recent study suggests that elevated soluble interleukin 2 receptor levels might correlate with patients with SLE and discoid lupus lesions (Blum et al. 1993).

Summary and Recommendations

Although there are laboratory features that are more prevalent in CLE vs SLE,there are no specific serologic tests that differentiate the two diseases. Clinical correlation is indispensable in distinguishing them. There are also important laboratory values that need to be monitored at the onset and during treatment of CLE with medications.

References

Black AJ, McLeod HL, Capell HA, Powrie RH, Matowe LK, Pritchard SC, Collie-Duguid ES, Reid DM (1998) Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 129:716–718 Blum C,Zillikens D,Tony HP,HartmannAA,BurgA (1993) Soluble interleukin-2 receptor as activity parameter in serum of systemic and discoid lupus erythematosus. Hautarzt 44:290–295 Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE (1993) Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Ann Intern Med 119:1198–1208 Callen JP (1982) Chronic cutaneous lupus erythematosus: clinical, laboratory, therapeutic, and prognostic examination of 62 patients. Arch Dermatol 118:412–416 Callen JP,Klein J (1988) Subacute cutaneous lupus erythematosus. Clinical, serologic, immunogenetic, and therapeutic considerations in 72 patients. Arthritis Rheum 31:1007–1013 Callen JP,Fowler JF,Kulick KB (1985) Serologic and clinical features of patients with discoid lupus erythematosus: relationship of antibodies to single-stranded deoxyribonucleic acid and of other antinuclear antibody subsets to clinical manifestations.J Am Acad Dermatol 13:748–755 Laboratory Features of Cutaneous Lupus Erythematosus 321

Callen JP,Kulick KB, Stelzer G, Fowler JF (1986) Subacute cutaneous lupus erythematosus. Clini- cal, serologic, and immunogenetic studies of 49 patients seen in a non-referral setting. J Am Acad Dermatol 15:1227–1237 Chelbus E, Wolska H, Blaszyk M, Jablonska S (1998) Subacute cutaneous lupus erythematosus versus systemic lupus erythematosus: diagnostic criteria and therapeutic implications. J Am Acad Dermatol 38:405–412 Choudhry V, Madan N, Sood SK, Ghai OP (1978) Chloroquine-induced haemolysis and acute renal failure in subjects with G-6-PD deficiency. Trop Geogr Med 30:331–335 Cohen MR, Crosby D (1994) Systemic disease in subacute cutaneous lupus erythematosus: a controlled comparison with systemic lupus erythematosus. J Rheumatol 21:1665–1669 Committee on Safety of Medicines/Medicines Control Agency (1997) Blood dyscrasias and other ADRs with low-dose methotrexate. Current Problems 23:12–18 Custer RP (1946) Aplastic anemia in soldiers treated with Atabrine (quinacrine). Am J Med Sci 212:211–224 Dahl MGC (1984) Folate depletion in psoriatics on methotrexate. Br J Dermatol 111(Suppl 26):18 Dodd HJ, Kirby JD, Munro DD (1985) Megaloblastic anaemia in psoriatic patients treated with methotrexate. Br J Dermatol 112:630–631 Ettinger WH, Hazzard WR (1988) Prednisone increases very low density lipoprotein and high density lipoprotein in healthy men. Metabolism 37:1055–1058 Fonseca E,Alvarez R, Gonzalez MR, Pascual D (1992) Prevalence of anticardiolipin antibodies in subacute cutaneous lupus erythematosus. Lupus 1:265–268 Franceschini F, Calzavara-Pinton P, Quinzanini M, Cavazzana I, Bettoni L, Zane C, Facchetti F, Airo P, McCauliffe DP, Cattaneo R (1998) Chilbains lupus erythematosus is associated with antibodies to SSA/Ro. Lupus 8:215–219 Gaffney K, Scott DG (1998) Azathioprine and cyclophasphamide in the treatment of rheumatoid arthritis. Br J Rheum 37:824–836 Johansson-Stephansson E, Koskimes S, Partanen J, Kariniemi AL (1989) Subacute cutaneous lupus erythematosus: genetic markers and clinical and immunological findings in patients. Arch Dermatol 125:791–796 Kersley GD, Palin AG (1959) Amodiaquine and hydroxychloroquine in rheumatoid arthritis. Lancet ii:886–888 Konstadoulakis MM, Kroubouzos G, Tosca A, Piperingos G, Marafelia P, Konstadoulakis M, Varelzidis A, Koutras DA (1993) Thyroid autoantibodies in the subsets of lupus erythematosus: correlation with other autoantibodies and thyroid function. Thyroidol Clin Exp 5:1–7 Kremer JM,Alarcon GS, Lightfoot RW Jr,Willkens RF,Furst DE,Williams HJ, Dent PB,Weinblatt ME (1994) Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 37:1829–1830 Landewe RB, Vergouwen MS, Goeei The SG, Van Rijthoven AW, Breedveld FC, Dijkmans BA (1995) Antimalarial drug induced decrease in creatinine clearance. J Rheumatol 22:34–37 Lee LA, Roberts CM, Frank MB, McCubbin VR, Reichlin M (1994) The autoantibody response to Ro/SSA in cutaneous lupus erythematosus. Arch Dermatol 130:1262–1268 Ludolph A, Matz DR (1982) Electrophysiologic changes in thalidomide neuropathy under treatment for discoid LE. EEG EMG 13:167–170 Mayou SC, Wojnorowska F, Lovell CR, Asherson RA, Leigh IM (1988) Anticardiolipin and antinuclear antibodies in discoid lupus erythematosus – their clinical significance. Clin Exp Der- matol 13:389–392 Meyerson MA, Cohen PR (1994) Dapsone-induced aplastic anemia in a woman with bullous systemic lupus erythematosus. Mayo Clin Proc 69:1159–1162 Millard LG, Rowell NR (1979) Abnormal laboratory test results and their relationship to prog- nosis in discoid lupus erythematosus. A long-term follow-up study of 92 patients. Arch Der- matol 115:1055–1058 Mok CC, Lau CS, Woon Sing Wong R (1998) Toxicities of dapsone in the treatment of cutaneous manifestations of rheumatic diseases. J Rheumatol 25:1246–1247 322 Shuntaro Shinada, Daniel J. Wallace

Musabayane CT, Ndhlovu CE, Balment RJ (1994) The effects of oral chloroquine administration on kidney function. Renal Fail 16:221–228 Neuberger J (1995) Methotrexate and liver disorders. Prescribers’ J 35:158–63 O’Loughlin S, Schroeter AL, Jordan RE (1978) A study of lupus erythematosus with particular reference to generalized discoid lupus. Br J Dermatol 99:1–11 Orth DN,Kovacs WJ (1998) The adrenal cortex.In:Wilson JD,Foster DW,Kronenberg HM,Larsen PR (eds) Williams textbook of endocrinology, 9th ed.WB Saunders, Philadelphia, pp 517–664 Petri M, Lakatta C, Magder L, Goldman D (1994) Effects of prednisone and hydroxychloroquine on coronary artery disease rise factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med 96:254–259 Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR (1991) Lupus erythematosus in the 1980s: a survey of 570 patients. Semin Arthritis Rheum 21:55–64 Polano MK, Cats A, van Olden GAJ (1965) Agranulocytosis following treatment with hydroxy- chloroqine sulfate. Lancet 1:1275 Provost TT, Ratrie H (1990) Autoantibodies and autoantigens in lupus erythematosus and Sjo- gren’s syndrome. Curr Probl Dermatol 2:150–208 Prystowsky SD, Kerndon JH, Gilliam JN (1975) Chronic cutaneous lupus erythematosus (DLE): a clinical and laboratory investigation of 80 patients. Medicine 55:183–191 Rowell NR (1984) The natural history of lupus erythematosus. Clin Exp Dermatol 9:217–231 Sanchez NP, Peters MS, Winkelmann RK (1981) The histopathology of lupus erythematosus panniculitis. J Am Acad Dermatol 5:673–680 Schimmer BP, Parker KL (1996) Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Hardman JE, Limbird LE, Molinoff PB, Ruddon RW,Gilman AG (eds) The pharmacologi- cal basis of therapeutics, 9th ed. McGraw-Hill, New York, pp 1459–1485 Shi SY,Feng SF,Liao KH, Fang L, Kang KF (1987) Clinical study of 30 cases of subacute cutaneous lupus erythematosus. Chin Med J 100:45–48 Sontheimer RD (1989) Subacute cutaneous lupus erythematosus: a decade’s perspective. Med Clin North Am 73:1073–1090 Sontheimer RD, Provost TT (1997) Cutaneous manifestations of lupus erythematosus. In: Wal- lace DJ, Hahn BH (eds) Dubois’ lupus erythematosus, 5th ed. Williams & Wilkins, Philadel- phia, pp 569–623 Sontheimer RD, Maddison PJ, Richlin M, Jordon RE, Stasny P, Gilliam JN (1982) Serologic and HLA associations in subacute cutaneous lupus erythematosus: a clinical subset of lupus erythematosus. Ann Intern Med 97:664–671 Sturdevant RA, Singleton JW,Derern JL, Law DH, McCleery JL (1979) Azathioprine-related pancreatitis in patients with Crohn’s disease. Gastroenterology 77:883–886 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) Special article: the 1982 revised criteria for the classification of systemic lupus erythmatosus. Arthritis Rheum 25:1271–1277 Tebbe B, Mansmann U, Wollina U, Auer-Grumbach P, Licht-Mbalyohere A, Arensmeier M, Orfanos CE (1997) Markers in cutaneous lupus erythematosus indicating systemic involvement–amulticenter study on 296 patients. Acta Derm Venereol 77:305–308 Wallace DJ (1989) The use of quinacrine (Atabrine) in rheumatic diseases: a reexamination. Semin Arthritis Rheum 18:282–296 Wallace DJ, Metzger AL, Stecher VJ, Turnbull BA, Kern PA (1990) Cholesterol-lowering effects of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids. Am J Med 89:322–326 Wallace DJ, Pistiner M, Nessim S, Metzger AL, Klinenberg JR (1992) Cutaneous lupus erythematosus without systemic lupus erythematosus: clinical and laboratory features. Semin Arthritis Rheum 21:221–226 Winkelmann RK, Peters MS (1982) Lupus panniculitis. Dermatol Update 135 Wysenbeek AJ, Guedj D, Amit M, Weinberger A (1992) Rash in systemic lupus erythematosus: prevalence and relation to cutaneous and non-cutaneous disease manifestations. Ann Rheum Dis 51:717–719